title: Presence of anaplastic lymphoma kinase in inflammatory breast cancer.
abstract: Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK(+) IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA ; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 1950, 1901 East Road, South Campus Research Building 4; Office 3.1009, Houston, TX 77230-1429 USA.
authors.forename: Fredika M
authors.initials: FM
authors.lastname: Robertson
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin Iii
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Van Laere
authors.forename: Francois
authors.initials: F
authors.lastname: Bertucci
authors.forename: Khoi
authors.initials: K
authors.lastname: Chu
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Fernandez
authors.forename: Zhaomei
authors.initials: Z
authors.lastname: Mu
authors.forename: Katherine
authors.initials: K
authors.lastname: Alpaugh
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.forename: Rita
authors.initials: R
authors.lastname: Circo
authors.forename: Julia
authors.initials: J
authors.lastname: Wulfkuhle
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Ye
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Boley
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Ricardo
authors.initials: R
authors.lastname: Moraes
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.forename: Ruggero
authors.initials: R
authors.lastname: Demaria
authors.forename: Sanford H
authors.initials: SH
authors.lastname: Barsky
authors.forename: Guoxian
authors.initials: G
authors.lastname: Sun
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
keywords: Anaplastic lymphoma kinase; Crizotinib; Inflammatory breast cancer; Reverse phase protein arrays